ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.1777C>T (p.Arg593Trp)

dbSNP: rs886039530
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255573 SCV000322273 pathogenic not provided 2024-08-02 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect by impacting the rate of phosphorylation from ATP and Na/K-ATPase activity (PMID: 16538223, 22117059); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23561701, 17495624, 27445835, 18184292, 18728015, 22117059, 20442779, 16538223, 34384358, 27535533)
Neurogenetics Laboratory - MEYER, AOU Meyer RCV000417013 SCV000494559 uncertain significance Epileptic encephalopathy 2016-11-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001213736 SCV001385385 pathogenic Familial hemiplegic migraine 2023-05-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 16538223, 22117059). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 265407). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 16538223). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 593 of the ATP1A2 protein (p.Arg593Trp).
Ambry Genetics RCV002518762 SCV003576530 uncertain significance Inborn genetic diseases 2021-09-27 criteria provided, single submitter clinical testing The c.1777C>T (p.R593W) alteration is located in exon 13 (coding exon 13) of the ATP1A2 gene. This alteration results from a C to T substitution at nucleotide position 1777, causing the arginine (R) at amino acid position 593 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV004796139 SCV005417127 likely pathogenic Migraine, familial hemiplegic, 2 criteria provided, single submitter clinical testing PM2_Supporting+PP3_Strong+PP2+PS4_Supporting

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